Effects of a Novel Archaeal Tetraether-Based Colipid on the In Vivo Gene Transfer Activity of Two Cationic Amphiphiles

Abstract

Gene therapy for treating inherited diseases like cystic fibrosis might be achieved using multimodular nonviral lipid-based systems. To date, most optimizations have concerned cationic lipids rather than colipids. In this study, an original archaeal tetraether derivative was used as a colipid in combination with one or the other of two monocationic amphiphiles. The liposomes obtained, termed archaeosomes, were characterized regarding lipid self-assembling properties, macroscopic/microscopic structures, DNA condensation/neutralization/relaxation abilities, and colloidal stability in the presence of serum. In addition, gene transfer experiments were conducted in mice with lipid/DNA complexes being administered via systemic or local delivery routes. Altogether, the results showed that the tetraether colipid can provide complexes with different in vivo transfection abilities depending on the lipid combination, the lipid/colipid molar ratio, and the administration route. This original colipid appears thus as an innovative modular platform endowed with properties possibly beneficial for fine-tuning of in vivo lipofection and other biomedical applications.

Efficient in vivo transfection and safety profile of a CpG-free and codon optimized luciferase plasmid using a cationic lipophosphoramidate in a multiple intravenous administration procedure

“…The human elongation factor-1 alpha promoter (EFIa) driving luc expression has already been extensively described in several in vivo studies as a nonsilenced promoter [11,12,19,24,25], but it was the first time that such CpG-free plasmid was evaluated with a cationic lipophosphoramidate in a repeated systemic administration procedure. Of note, under similar experimental conditions, the slightly less efficient monounsaturated lipophosphoramidate derivative KLN-47 gave rise to approximately 13 days of transgene expression in lungs after a single intravenous injection [26].…”

Synthesis of a novel archaeal tetraether-type lipid containing a diorthoester group as a helper lipid for gene delivery

“…at the proportion that led to the best transfection efficiency with the non-cleavable Tetraether 2. 20 Hydration of lipid films constituted of a mixture of MM18/3 10:1 permitted to prepare liposomal formulations which were then converted into lipoplexes with various charge ratios (DNA/cationic lipid ratios, i.e. +/-ratios) by mixing these lipid vesicles with DNA aqueous solutions.…”

“…Indeed, when combined with the cationic lipids, monopolar diethers are supposed to exhibit hexagonal phases, 24 unlike tetraethers which facilitate the formation of lamellar phases. 20 As a consequence, the change in lipid membrane organization provided by this chemical transformation of tetraethers into diethers, could promote the endosomal release. The present work describes the synthesis of this new diorthoester-based tetraether 3 and the preliminary studies related to its efficiency to complex and to deliver plasmid DNA (pDNA) in in vitro assays when this novel helped lipid was combined with cationic lipid MM18.…”

Recent progress in gene therapy to deliver nucleic acids with multivalent cationic vectors

“…3 shows a tipical plot of size vs the charge ratio of the nano-aggregate formed by the (C 12 Am) 2 C 12 -siRNA lipoplex [114]. This procedure has been followed to get the size for: (a) lipoplexes formed by pDNA with GCLs [64,66,111,115,137] or MVCLs [138,139]; (b) polyplexes formed by pDNA with cationic polymers [95,98,[124][125][126]140] or polycations [134,141,142]; (c) lipoplexes formed by siRNA with GCLs [114] or MVCLs [139,143]; and (d) polyplexes formed by siRNA with cationic polymers [90,105,144] or polycations [145]. Additionally, SLS and DLS methods also provide an estimation of the electroneutrality ratio of the nanoaggregates because, at this point (see Fig.…”

“…As a result of that, the transfection capability [75]. Recent studies reporting TE of lipoplexes and polyplexes have been investigated: (i) divalent GCLs, as cholesterol-based with alkyl or oligooxyethylene spacers [118,119,121], aromatic-based with alkyl or oligo-oxyethylene spacers [46,93], SS14 linkers [66], ammonium with alkyl or oligo-oxyethylene spacers [54,71,93,179], imidazolium or pyridinium derivatives with alkyl-or oligooxyethylene spacers [45,59,75], aminoacid-based [62,64] or gemini-like amphiphilic peptides [150], cyclen-based CLs [120,180], and archael tetraether-based lipids [138];…”